Protein kinases represent a large family of proteins, which play a central role in the regulation of a wide variety of cellular processes, and so maintain control over cellular function. These kinases includes Akt, Axl, Aurora A, Aurora B, Aurora C, dyrk2, epha2, fgfr3, flt-3, vegfr3, igf1r, IKK2, JNK3, Vegfr2, MEK1, MET, P70s6K, Plk1, RSK1, Src, TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, PDGFR, TAK1, LimK, Flt3, Flt1, PDK1 and Erk, among others. Inhibition of such kinases has become an important therapeutic targeting tool.
Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include cancers, autoimmune, inflammatory, cardiovascular, neurological and neurodegenerative diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
The compounds of the present invention are novel, selective, and highly potent ATP-competitive inhibitors of Aurora kinases (A, B and C), and protein kinases TrkA, TrkB, Flt3(D835Y)(h), Ret(h), IRAK4(h), FAK(h), KDR9H0, PYK(2)(h) and Tie2(K849w). The Aurora family of conserved serine/threonine kinases perform essential functions during cell division. The three mammalian paralogues are very similar in sequence, but differ significantly in their localization, function, substrates and regulatory partners.
Aurora A is mainly associated with the spindle poles during mitosis, where it is required for centrosome separation and maturation (Sausville E A. Nat. Med., (2004) 10:234-235). Aurora A also functions in meiosis by promoting oocyte maturation, polar-body extrusion, spindle positioning and exit from metaphase I. Aurora B is a chromosomal-passenger protein with multiple functions in mitosis. It is required for phosphorylating histone H3, targeting condensing, and compacting normal chromosomes. It has also been recently shown to be essential for chromosome biorientation, kinetochore-microtubule interactions and the spindle-assembly checkpoint. Aurora B is essential for completion of cytokinesis. Much less is known about Aurora C kinase, other than that it seems to be preferentially expressed in meiotic cells. Aurora kinases appear to provide an additional level of regulation that might be essential for the choreography of mitotic events.
Aurora kinases are overexpressed in certain types of cancers, including colon, breast, pancreatic, ovarian and other solid-tumor cancers. The genes encoding the Aurora A and B kinases tend to be amplified in certain types of cancers, while the gene encoding the Aurora C kinase resides in a region of the chromosome that is subject to rearrangement and deletion. Aurora A has been associated with a variety of malignancies, including primary colon, colorectal, breast, stomach, ovarian, prostate, and cervical cancer, neuroblastoma, and other solid-tumor cancers (Warner et al. (2003) Molecular Cancer Therapeutics 2:589-95). Since Aurora A and B kinases are frequently elevated or overexpressed in human cancers makes them attractive targets for therapeutic intervention (Mountzios et al., Cancer Treatment Reviews (2008) 34:175-82; Gautschi et al., Clin. Cancer Res. (2008), 14(6):1639-48; Mortlock et al., Current Topics in Medicinal Chemistry (2005), 5:807-21).
TrkA, or Tropomycin-related kinase A, TrkB and TrkC are all members of a sub-family of protein kinases important for neuronal growth and differentiation. TrkA is a high affinity receptor kinase for Nerve Growth Factor (NGF), and so plays a vital role in neuronal differentiation and survival. It is believed to be important in cancers, mental retardation, and insensitivity to pain. TrkB is activated by “Brain Derived Neurotrophic Factor” of “BDNF”, and likewise is important in cancers and conditions involving neuronal survival.
Flt3 is a receptor tyrosine kinase that is expressed on hematopoietic progenitors, B-cell precursor cells, and macrophage precursor cells. Thus, Flt3 has important functions in hematopoietic progenitor proliferation and survival, macrophage cellular differentiation, and dendritic cell differentiation. It is overexpressed in acute myeloid leukaemia (AML), and has been shown to be mutated in other hematopoietic diseases.
Ret(h) is a receptor tyrosine kinase for glial cell line-derived neurotrophic factors of extracellular signalling molecules. Loss of function mutations associated with this family of kinases are related to development of Hirschsprung's disease, while overexpression of Ret(h) is associated with cancers, including medullar thyroid carcinoma, parathyroid tumors, endocrine neoplasias types II and III, and phaeochromocytoma.
IRAK4(h), interleukin-1-receptor-associated kinase-4, is one member of the IRAK family needed for activation of the Interleukin-1 (IL-1) pathway. Qin et al. have shown that kinase activity of IRAK and IRAK4 are redundant for IL-1 mediated signalling, but IRAK4 is required for the efficient recruitment of IRAK to the IL-1 receptor complex (Qin et al., J. Biol. Chem., 279(25):26748-53 (Jun. 18, 2004). Malfunctioning of the IL-1 pathway can result in problems with fever and inflammation, immune system deficiencies and infections via non-functioning lymphocytes, rheumatoid arthritis, degenerative bone disease, and Alzheimer's disease.
The Focal Adhesion Kinase, FAK, acts in cellular adhesion, motility and survival. It is a non-receptor tyrosine kinase that was identified originally as a substrate for the oncogene protein tyrosine kinase, v-src, but is now believed also to play a role in anchoring cytoskeletons, and hence its association with cancers. PYK-2 also is a member of the FAK family, and is named for being a proline-rich tyrosine kinase. Also called “related adhesion focal tyrosine kinase”, “cell adhesion kinase” and “calcium-dependent tyrosine kinase”, PYK-2 is found in fewer types of cells compared to FAK, but its expression is high in neural, epithelial and hematopoietic cells, in natural killer cells, B and T lymphocytes, and megakaryocytes. Thus, it plays an important role in immune and inflammatory responses and in cellular polarization via cytoskeletal reorganization in lymphocytes; 15 Aug. 8).
KDR or or “kinase insert domain receptor” is a type III receptor tyrosine kinase, and is ubiquitous throughout the body. Hence, its overexpression is associated with cancers of various types, rheumatoid arthritis, bone and mental diseases among others.
Tie-2 along with the co-member of its family, Tie-1, is a receptor protein kinase that is expressed in developing vascular endothelial cells. Tie-2 is especially important in angiogenesis for development of vascular networks among endothelial cells, while Tie-1 is more important in establishing vascular structural integrity, the loss of which results in hemorrhage and edema (Sato et al., Nature, 1995, 376(6535):70-74).
A limited number of macrocyclic compound inhibitors of protein kinases have been reported. For example, Schering AG teaches macrocyclic anilino-pyrimidine compounds that have a substituted sulfoximine moiety and that selectively inhibit type 2 cell kinases like Aurora kinases while also acting as selective inhibitors of type 1 cell kinases such as cyclin-dependent kinases (WO 2007/079982). Eisai Co., Ltd., claims marcrocyclic compounds having an optionally substituted benzoyl moiety that are useful in the treatment of malignancies, angiogenesis, inflammatory and autoimmune disorders (WO 03/076424). Cyclin-dependent protein kinases such as CDK2 and CKD5 are inhibitied by macrocyclic pyridyl-pyrimidineamine derivatives, as taught by IRM LLC (WO 04/078682). Abbott Laboratories teaches cancer-treating protein kinase inhibitors that are benzodioxatriazacycloheptadecine carbonitrile derivatives (US 2005/0215556; WO 05/047294), Bayer Schering Pharma AG describes pyrimidine benzenecyclonaphthanlenylsulfoximide derivatives that are selective inhibitors of Aurora kinases (EP 1 803 723), and Janssen Pharmaceutica N.V. teaches 2,4 (4,6) pyrimidine macrocycles for the treatment of cancers, diabetes, inflammation and arthritis (WO 06/061415).
Thus, the identification of additional and more effective macrocyclic inhibitors of protein kinases and Aurora kinases in particular is a goal of the present invention. Another goal is to provide derivatives that actively inhibit disturbed, uncontrolled or unregulated Aurora kinase activity.
These compounds and pharmaceutical compositions comprising them are presented either individually or in kit form. Also contained herein are methods for using the same for treating proliferative disorders, such as cancers, psoriasis, viral and bacterial infections, vascular restinosis, inflammatory and autoimmune diseases, that result from unregulated and uncontrolled cellular proliferation.
Included in this invention are processes for preparing the macrocyclic derivative compounds that actively inhibit unregulated Aurora kinase activity.
Additional objects, features and advantages of the present invention will become apparent to those skilled in the art from the following description and claims.